【作者】 李文通；

【导师】 周庚寅；

【作者基本信息】 山东大学 ， 病理学与病理生理学， 2006， 博士

【摘要】 [背景与目的] 肿瘤多药耐药(multidrug resistance，MDR)系指肿瘤细胞对一种抗肿瘤药物产生抗药性的同时，对其他多种结构不同、作用靶位不同、作用机制不同的抗肿瘤药物产生交叉耐药性。MDR在癌症病人中是一种常见的现象，随着肿瘤化疗药物的广泛应用，肿瘤的耐药性问题也越来越突出，已成为肿瘤有效治疗的主要障碍之一。MDR的发生机制复杂，其中ATP结合盒式(ATP binding cassette，ABC)转运蛋白与耐药密切相关，这些蛋白包括P-糖蛋白(P-glycoprotein，P-gp)、肺耐药蛋白(lung resistance protein，LRP)、MRP(multidrug resistance protein，MRP)以及它的类似蛋白MRP2和MRP3等。乳腺癌耐药蛋白(breast cancer resistant protein，BCRP)是一种新发现的ABC转运蛋白家族的成员，过表达BCRP可以导致肿瘤细胞系对米托蒽醌、拓扑替康、阿霉素等药物的耐药。 如何逆转MDR是治疗肿瘤的主要难题，化学抑制剂可以部分恢复肿瘤细胞对化疗药物的敏感性，现在也已经报到了许多BCRP抑制剂，但这些化学药物在达到治疗浓度时往往有较大的毒性；而且，肿瘤细胞还可以对这些化疗药物产生耐药。选择性降解mRNA来阻断耐药蛋白的生物合成，是一类低毒、有效逆转多药耐药的方法，具有良好的应用前景。在以更多还原

【Abstract】 [Background and objective]Human cancer cells can exhibit a cross-resistant phenotype against several unrelated drugs that differ widely with respect to molecular structure and target specificity. This phenomenon has been termed multidrug resistance (MDR). MDR, a common phenomenon in cancer patients, is the major obstacle in the successful treatment of cancer. Although the mechanistic basis for this phenomenon is complex, the overexpression of ABC transporters is often associated with this phenotype. Various members of the protein superfamily of ABC transporters have been associated with MDR of human cancers when overexpressed, including P-gp, the MRP and its homologues MRP2 and MRP3. BCRP is a relatively new member of the ABC-transporter family and overexpressed in a variety of human MDR cancer cell lines. Elevated expression of BCRP results in resistance to antitumor drugs, including mitoxantrone, topotecan, daunorubicin, doxorubicin and bisantrene etc.Reversal of MDR is a major goal in the clinical management of cancer. Pharmacological inhibition of the ABC transporters can be expected to resensitize cells to the action of antitumor agents. Inhibitors of BCRP have been reported. An alternative procedure to circumvent BCRP-mediated MDR更多还原